Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes

Mol Genet Metab. 2013 Jul;109(3):260-8. doi: 10.1016/j.ymgme.2013.04.006. Epub 2013 Apr 17.

Abstract

Cerebral creatine deficiency syndromes (CCDS) are a group of inborn errors of creatine metabolism that involve AGAT and GAMT for creatine biosynthesis disorders and SLC6A8 for creatine transporter (CT1) deficiency. Deficiencies in the three enzymes can be distinguished by intermediate metabolite levels, and a definitive diagnosis relies on the presence of deleterious mutations in the causative genes. Mutations and unclassified variants were identified in 41 unrelated patients, and 22 of these mutations were novel. Correlation of sequencing and biochemical data reveals that using plasma guanidinoacetate (GAA) as a biomarker has 100% specificity for both AGAT and GAMT deficiencies, but AGAT deficiency has decreased sensitivity in this assay. Furthermore, the urine creatine:creatinine ratio is an effective screening test with 100% specificity in males suspected of having creatine transporter deficiency. This test has a high false-positive rate due to dietary factors or dilute urine samples and lacks sensitivity in females. We conclude that biochemical screening for plasma GAA and measuring of the urine creatine:creatinine ratio should be performed for suspected CCDS patients prior to sequencing. Also, based on the results of this study, we feel that sequencing should only be considered if a patient has abnormal biochemical results on repeat testing.

MeSH terms

  • Amidinotransferases / blood
  • Amidinotransferases / chemistry
  • Amidinotransferases / deficiency*
  • Amidinotransferases / genetics
  • Amidinotransferases / metabolism
  • Amino Acid Metabolism, Inborn Errors / diagnosis*
  • Amino Acid Metabolism, Inborn Errors / genetics
  • Amino Acid Metabolism, Inborn Errors / metabolism
  • Brain Diseases, Metabolic, Inborn / diagnosis*
  • Brain Diseases, Metabolic, Inborn / genetics
  • Brain Diseases, Metabolic, Inborn / metabolism
  • Creatine / deficiency*
  • Creatine / genetics
  • Creatine / metabolism
  • Creatinine / urine
  • Developmental Disabilities / diagnosis
  • Developmental Disabilities / genetics
  • Developmental Disabilities / metabolism
  • Female
  • Guanidinoacetate N-Methyltransferase / blood
  • Guanidinoacetate N-Methyltransferase / deficiency*
  • Guanidinoacetate N-Methyltransferase / genetics
  • Guanidinoacetate N-Methyltransferase / metabolism
  • Humans
  • Intellectual Disability / diagnosis*
  • Intellectual Disability / genetics
  • Intellectual Disability / metabolism
  • Language Development Disorders / diagnosis*
  • Language Development Disorders / genetics
  • Language Development Disorders / metabolism
  • Male
  • Membrane Transport Proteins / genetics
  • Mental Retardation, X-Linked / diagnosis*
  • Mental Retardation, X-Linked / genetics
  • Mental Retardation, X-Linked / metabolism
  • Models, Molecular
  • Movement Disorders / congenital*
  • Movement Disorders / diagnosis
  • Movement Disorders / genetics
  • Movement Disorders / metabolism
  • Mutation
  • Phenotype
  • Plasma Membrane Neurotransmitter Transport Proteins / deficiency*
  • Plasma Membrane Neurotransmitter Transport Proteins / genetics
  • Plasma Membrane Neurotransmitter Transport Proteins / metabolism
  • Protein Conformation
  • Speech Disorders / diagnosis*
  • Speech Disorders / genetics
  • Speech Disorders / metabolism
  • Syndrome

Substances

  • Membrane Transport Proteins
  • Plasma Membrane Neurotransmitter Transport Proteins
  • creatine transporter
  • Creatinine
  • Guanidinoacetate N-Methyltransferase
  • Amidinotransferases
  • Creatine

Supplementary concepts

  • Arginine-Glycine Amidinotransferase Deficiency
  • Creatine deficiency, X-linked
  • Guanidinoacetate methyltransferase deficiency